Ronald D. Barr

Multiattribute Utility Function for a Comprehensive Health Status Classification System Health Utilities Index Mark 2

The Health Utilities Index Mark 2 (HUI:2) is a generic multiattribute, preference-based system for assessing health-related quality of life. Health Utilities Index Mark 2 consists of two components: a seven-attribute health status classification system and a scoring formula. The seven attributes are sensation, mobility, emotion, cognition, self-care, pain, and fertility. A random sample of general population parents were interviewed to determine cardinal preferences for the health states in the system. The health states were defined as lasting for a 60-year lifetime, starting at age 10. Values were measured using visual analogue scaling. Utilities were measured using a standard gamble technique. A scoring formula is provided, based on a multiplicative multiattribute utility function from the responses of 194 subjects. The utility scores are death-anchored (death = 0.0) and form an interval scale. Health Utilities Index Mark 2 and its utility scores can be useful to other researchers in a wide variety of settings who wish to document health status and assign preference scores.

The Health Utilities Index (HUI®) system for assessing health-related quality of life in clinical studies

This paper reviews the Health Utilities Index (HUI? systems as means to describe health status and obtain utility scores reflecting health-related quality of life (HRQoL). The HUI Mark 2 (HUI2) and Mark 3 (HUI3) classification and scoring systems are described. The methods used to estimate multiattribute utility functions for HUI2 and HUI3 are reviewed. The use of HUI in clinical studies for a wide variety of conditions in a large number of countries is illustrated. HUI provides a comprehensive description of the health status of subjects in clinical studies. HUI has been shown to be a reliable, responsive and valid measure in a wide variety of clinical studies. Utility scores provide an overall assessment of the HRQoL of patients. Utility scores are also useful in cost-utility analyses and related studies. General population norm data are available. The widespread use of HUI facilitates the interpretation of results and permits comparisons. HUI is a useful tool for assessing health status and HRQoL in clinical studies.

The distinctive biology of cancer in adolescents and young adults

One explanation for the relative lack of progress in treating cancer in adolescents and young adults is that the biology of malignant diseases in this age group is different than in younger and older persons, not only in the spectrum of cancers but also within individual cancer types and within the patient (host). Molecular, epidemiological and therapeutic outcome comparisons offer clues to this distinctiveness in most of the common cancers of adolescents and young adults. Translational and clinical research should not assume that the biology of cancers and patients is the same as in other age groups, and treatment strategies should be tailored to the differences.

Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985–2000)

The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic leukemia (ALL) Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20–30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985 and 2000, 1457 children aged 0–18 years were treated on four consecutive protocols: 85-01 (1985–1987), 87-01 (1987–1991), 91-01 (1991–1955) and 95-01 (1996–2000). The 10-year event-free survival (EFS)±s.e. by protocol was 77.9±2.8% (85-01), 74.2±2.3% (87-01), 80.8±2.1% (91-01) and 80.5±1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (P=0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79–85% for T-cell ALL patients and 75–78% for adolescents (age 10–18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely affecting EFS or OS in high-risk (HR) patients, and frequently dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk (SR) patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

Children, cancer, and nutrition—A dynamic triangle in review

The overall cure rate for cancer in childhood now exceeds 70% and is projected to reach 85% by the year 2010 in industrialized countries. Therefore, major attention is being placed on reducing the side effects of therapy. However, 85% of the worlds children live in developing countries, where access to adequate care often is limited and health status frequently is influenced adversely by prevalent infectious diseases and malnutrition. Despite several confounding factors (different definitions of nutritional status, the wide variety of measures used for its assessment, the selection biases by disease and stage, treatment protocols of variable dose intensity and efficacy, small sample sizes of the studies conducted in the last 20 years), it is accepted that the prevalence of malnutrition at diagnosis averages 50% in children with cancer in developing countries; whereas, in industrialized countries, it is related to the type of tumor and the extent of the disease, ranging from < 10% in patients with standard‐risk acute lymphoblastic leukemia to 50% in patients with advanced neuroblastoma. The importance of nutritional status in children with cancer is related to its possible influence on the course of the disease and survival. Some authors have described decreased tolerance of chemotherapy associated with altered metabolism of antineoplastic drugs, increased infection rates, and poor clinical outcome in malnourished children. In this article, the authors review methods of nutritional assessment and the pathogenesis of nutritional morbidity in children with cancer as well as correlations of nutritional status with diagnosis, treatment, and outcome. Cancer 2004;100:677–87.

Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995).

The Dana-Farber Cancer Institute (DFCI) ALL consortium has been conducting clinical trials in childhood acute lymphoblastic leukemia (ALL) since 1981. The treatment backbone has included intensive, multi-agent remission induction, early intensification with weekly, high-dose asparaginase, cranial radiation for the majority of patients, frequent vincristine/ corticosteroid pulses during post-remission therapy, and for high-risk patients, doxorubicin during intensification. Between 1981 and 1995, 1255 children with newly diagnosed ALL were evaluated on four consecutive protocols: 81-01 (1981–1985), 85-01 (1985–1987), 87-01 (1987–1991) and 91-01 (1991–1995). The 5-year event-free survival (EFS) rates (± standard error) for all patients by protocol were as follows: 74 ± 3% (81-01), 78 ± 3% (85-01), 77 ± 2% (87-01) and 83 ± 2% (91-01). The 5-year EFS rates ranged from 78 to 85% for patients with B-progenitor phenotype retrospectively classified as NCI standard-risk, 63–82% for NCI high-risk B-progenitor patients, and 70–79% for patients with T cell phenotype. Results of randomized studies revealed that neither high-dose methotrexate during induction (protocol 87-01) nor high-dose 6-mercaptopurine during intensification (protocol 91-01) were associated with improvement in EFS compared with standard doses. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

Favorable Outcome for Adolescents With Acute Lymphoblastic Leukemia Treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols

PURPOSE Historically, adolescents with acute lymphoblastic leukemia (ALL) have had inferior outcomes when compared with younger children. We report the outcome of adolescents treated on Dana-Farber Cancer Institute (DFCI; Boston, MA) ALL Consortium Protocols conducted between 1991 and 2000. PATIENTS AND METHODS A total of 844 patients aged 1 to 18 years, with newly diagnosed ALL were enrolled onto two consecutive DFCI-ALL Consortium Protocols. We compared outcomes in three age groups: children aged 1 to 10 years (n = 685), young adolescents aged 10 to 15 years (n = 108), and older adolescents aged 15 to 18 years (n = 51). RESULTS With a median follow-up of 6.5 years, the 5-year event-free survival (EFS) for those aged 1 to 10 years was 85% (SE, 1%), compared with 77% (SE, 4%) for those aged 10 to 15 years, and 78% (SE, 6%) for those aged 15 to 18 years (P = .09). Adolescents were more likely to present with T-cell phenotype (P < .001) and less likely to have the TEL-AML1 fusion (P = .05). The incidence of pancreatitis and thromboembolic complications, but not asparaginase allergy, was higher in patients 10 years of age compared with those younger than 10 years. However, there was no difference in the rate of treatment-related complications between the 10- to 15-year and 15- to 18-year age groups. CONCLUSION Adolescents were more likely to present at diagnosis with biologically higher risk disease (T-cell phenotype and absence of the TEL-AML1 fusion) and more likely to experience treatment-related complications than younger children. However, the 5-year EFS for older adolescents was 78% +/- 6%, which is superior to published outcomes for similarly aged patients treated with other pediatric and adult ALL regimens. Based on this experience, we currently are piloting our regimen in patients aged 18 to 50 years.

Mineral homeostasis and bone mass at diagnosis in children with acute lymphoblastic leukemia

OBJECTIVE To determine whether the osteopenia and unusual fractures observed in children with acute lymphoblastic leukemia (ALL) were related to the disease rather than to its treatment. DESIGN Prospective analysis of the bone and mineral status in 40 consecutive children with ALL seen in a pediatric tertiary-care referral center. METHODS Biochemical indicators of mineral, endocrine, and vitamin D status were measured before initiation of therapy. Bone mass was determined radiographically and by dual-photon absorptiometry of the lumbar region of the spine (L2-L4). Correlations between clinical observations, leukemia variables, bone mass, and biochemical assessment were determined. RESULTS At the time of diagnosis musculoskeletal pain was present in 36% of patients and was more common in children with CD10-positive leukemia and leukocyte counts less than 20 x 10(9) cells/L. Radiographic evidence of osteopenia and fractures was observed in 13% and 10% of children, respectively. The mean bone mineral content was normal. Bone mass measurement z scores correlated with plasma 1,25-dihydroxyvitamin D3 concentrations (r = 0.43, p < 0.05). Plasma calcium, magnesium, phosphorus, and 25-hydroxyvitamin D3 levels were normal. Low plasma osteocalcin (mean +/- SD, 1.6 +/- 1.6 nmol/L) and 1,25-dihydroxyvitamin D3 (33.4 +/- 26.4 pmol/L) values were observed. Parathyroid hormone levels were low in 14% of children. Hypercalciuria was detected in 64% of children. Urinary deoxypyridinoline was lower (p < 0.01) than in age-matched control subjects. Histomorphometric measurements of iliac bone showed abnormalities in mineralization in the biopsy specimens from three of nine children. CONCLUSION Most children with ALL have alterations in bone metabolism and bone mass when first examined. These data suggest defective mineralization as the mechanism for decreased bone mass and implicate the leukemic process as causative.

Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition.

In children with acute lymphoblastic leukemia (ALL), abnormalities in mineral homeostasis and bone mass were first reported by our group in the late 1980s. Prospective longitudinal cohort studies in 40 consecutive patients receiving treatment according to the Dana‐Farber Cancer Institute (DFCI) protocol 87‐001 and 16 children receiving DFCI protocol 91‐001 afforded us the opportunity to explore various etiologies of the observed abnormalities in mineral and bone metabolism, specifically the leukemic disease process and chemotherapeutic drugs such as steroids and aminoglycoside antibiotics. At diagnosis of ALL, >70% of children had abnormally low plasma 1,25‐dihydroxyvitamin D, 73% had low osteocalcin and 64% had hypercalciuria, indicating an effect of the leukemic process on vitamin D metabolism and bone turnover. During remission induction, treatment with high‐dose steroid (prednisone or dexamethasone) resulted in further reduction in plasma osteocalcin and elevated parathyroid hormone levels. During 24 months of chemotherapy‐maintained remission, reduction in bone mineral content (BMC), as measured by Z‐scores, occurred in 64% of children, most severely affecting those >11 years of age. A reduction in BMC during the first 6 months had a positive predictive value of 64% for subsequent fracture. By the end of 2 years of therapy, fractures occurred in 39% of children and radiographic evidence of osteopenia was found in 83% of the entire study group. Investigations of the biochemical basis of the bone abnormalities revealed that by 6 months hypomagnesemia developed in 84% of children (of whom 52% were hypermagnesuric) and plasma 1,25‐dihydroxyvitamin D remained abnormally low in 70%. Altered magnesium status was attributed to renal wastage of magnesium following cyclical prednisone therapy and treatment with aminoglycoside antibiotics such as amikacin for fever accompanying neutropenia. Dietary intake and absorption of magnesium were normal. In 10 children treated for hypomagnesemia with supplemental magnesium for up to 16–20 weeks, plasma magnesium normalized in only 50% of subjects. Int. J. Cancer Supplement 11:35–39, 1998.

Skeletal Morbidity in Childhood Acute Lymphoblastic Leukemia

PURPOSE Treatment for acute lymphoblastic leukemia (ALL) in childhood results in a reduction in bone mineral density (BMD). Whether there is a recovery of this lost bone mass in survivors of ALL is not known. We sought to determine if changes in BMD are common long-term sequelae in children with ALL. METHODS Bone mineral densitometry of the lumbar spine and femoral neck was performed on 106 patients. The results were compared with those of age-matched normal controls. The effect of treatment was examined in those with low BMD compared with the remainder of the study group. RESULTS When data were tested with respect to age, sex, and age and sex, no difference was observed in BMD between survivors of childhood ALL and controls. In the subgroup of patients with low BMD, the difference was not related to age, age at diagnosis, or years since diagnosis. Low BMD of the spine was not explained by radiotherapy (RT), methotrexate (MTX) dose, or corticosteroid dose. Low BMD of the femur was not explained by RT. However, those with low femoral BMD were more likely to have received high-dose MTX or higher-dose corticosteroids compared with the remainder of the group. CONCLUSION It appears that survivors of childhood ALL as a whole recover normal BMD. However, those patients who received a total MTX dose of greater than 40000 mg/m(2) or a total corticosteroid dose of greater than 9000 mg/m(2) may not recover normal BMD and therefore should be screened for decreased BMD of the femoral neck.